Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F16%3A00469893" target="_blank" >RIV/61388963:_____/16:00469893 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1002/slct.201601679" target="_blank" >http://dx.doi.org/10.1002/slct.201601679</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/slct.201601679" target="_blank" >10.1002/slct.201601679</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase

Popis výsledku v původním jazyce

Drug resistant uropathogenic E. coli associated with urinary tract infections (UTIs) are a serious and debilitating health threat. Therefore new drug targets to treat this disease need to be explored. One possible approach is to block the synthesis of the nucleoside monophosphates required for DNA/RNA production in these pathogens. In E. coli, the purine salvage pathway has two 6-oxopurine phosphoribosyltransferases (PRTs), xanthine-guanine PRT (EcXGPRT) and hypoxanthine PRT (EcHPRT). Here, we investigate acyclic nucleoside phosphonates (ANPs) as inhibitors of EcHPRT and have determined six crystal structures of EcHPRT in complex with ANPs. These data reveal the binding modes of these compounds and can assist in future rational structure-based design efforts. It is suggested that a combination of inhibitors that block de novo and salvage pathways is a plausible approach to developing new antibiotics for E. coli UTIs. In addition, we provide details of a novel approach to accelerating the crystallization of this enzyme that may be of general applicability for rational drug discovery.

Název v anglickém jazyce

Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase

Popis výsledku anglicky

Drug resistant uropathogenic E. coli associated with urinary tract infections (UTIs) are a serious and debilitating health threat. Therefore new drug targets to treat this disease need to be explored. One possible approach is to block the synthesis of the nucleoside monophosphates required for DNA/RNA production in these pathogens. In E. coli, the purine salvage pathway has two 6-oxopurine phosphoribosyltransferases (PRTs), xanthine-guanine PRT (EcXGPRT) and hypoxanthine PRT (EcHPRT). Here, we investigate acyclic nucleoside phosphonates (ANPs) as inhibitors of EcHPRT and have determined six crystal structures of EcHPRT in complex with ANPs. These data reveal the binding modes of these compounds and can assist in future rational structure-based design efforts. It is suggested that a combination of inhibitors that block de novo and salvage pathways is a plausible approach to developing new antibiotics for E. coli UTIs. In addition, we provide details of a novel approach to accelerating the crystallization of this enzyme that may be of general applicability for rational drug discovery.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GA16-06049S" target="_blank" >GA16-06049S: Inhibitory 6-oxopurin fosforibosyltransferáz založené na acyklických nukleosidfosfonátech: potenciální nové antibakteriální a antiparazitické látky</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ChemistrySelect

ISSN

2365-6549

e-ISSN

—

Svazek periodika

1

Číslo periodika v rámci svazku

19

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

10

Strana od-do

6267-6276

Kód UT WoS článku

000395432100030

EID výsledku v databázi Scopus

2-s2.0-85021431307